The G-protein coupled receptor (GPCR), TGR5 (aka M-BAR) was independently discovered by two groups [Kawamata Y. et al, J. Biol. Chem., 278:9435-9440, 2003; Maruyama T. et al. Biochem. Biophs. Res. Commun. 298, 714-719, 2002]. TGR5 is a seven transmembrane Gs-coupled GPCR and stimulation by ligand binding causes activation of adenylyl cyclase which leads to the elevation of intracellular cAMP and subsequent activation of downstream signaling pathways. Maruyama et al. [Maruyama T. et al. Biochem. Biophs. Res. Commun. 298, 714-719, 2002] showed that TGR5 is expressed in intestinal enteroendocrine cell lines from human (NCI-H716) and murine (STC-I, GLUTag) origin, but not in the intestinal epithelial cells (CaCo-2 and HT-29). Stimulation of TGR5 by bile acids (BA) in NCI-H716 cells stimulated cAMP production. This suggested that bile acids may induce the secretion of glucagon-like peptide-1 (GLP-I) or cholecystokinin (CCK) from the enteroendocrine cells through TGR5 stimulation, since cAMP stimulated the secretion of GLP-I and CCK from these cells [Reimer R. A. et al. Endocrinology 142, 4522-4528, 2001; Chang C H. et al. Am. J. Physiol. 271, G516-G523, 1996; Brubaker P X. et al, Endocrinology 139, 4108-4114, 1998]. Additional work by Katsuma S. et al. has demonstrated that activation of TGR5 by BA promoted release of GLP-I in STC-I cells [Katsuma S. et al. Biochem. Biophys. Res. Commun. 329, 386-390, 2005]. RNA interference experiments revealed that reduced expression of TGR5 resulted in reduced secretion of GLP-I. GLP-I has been shown to stimulate insulin release in a glucose dependent manner in humans [Kreymann et al. Lancet 2 (8571) 1300-1304, 1987], and studies in experimental animals demonstrated that this incretin hormone is necessary for normal glucose homeostasis. In addition, GLP-I can exert several beneficial effects in diabetes and obesity, including 1) increased glucose disposal, 2) suppression in glucose production, 3) reduced gastric emptying, 4) reduction in food intake and 5) weight loss.
Recently published data suggested that activation of TGR5 might be beneficial for the treatment of obesity and diabetes. Watanabe et al. (Nature, 439, 484-489, 2006) reported that mice fed high fat diet (HFD) containing 0.5% cholic acid gained less weight than control mice on HFD alone. There was no difference between the two groups in terms of food intake. These effects were independent of FXR-alpha, and instead stem from the binding of bile acids to TGR5 and the subsequent induction of the cAMP-dependent thyroid hormone activating enzyme type 2 (D2) which converts the inactive T3 into active T4, leading to stimulation of the thyroid hormone receptor and promoting energy expenditure. Mice lacking the D2 gene (D2˜˜) were resistant to cholic acid-induced weight loss. In both rodents and humans, the most thermogenically important tissues (the brown adipose and skeletal muscle) are specifically targeted by this mechanism because they co-express D2 and TGR5. The BA-TGR5-cAMP-D2 signaling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control. Taken together, a small molecule TGR5 modulator could be used for the treatment of obesity, diabetes and a wide range of acute and chronic inflammatory diseases. Thomas et al. Cell Metabolism 10, 167-177 2009.
In addition, certain substituted heterocyclic compounds have been described as agonists of TGR5 for the treatment of metabolic, cardiovascular, and inflammatory diseases. (EP01/591120A1, WO04/043468A1, WO04/067008A1, and JP24346059A2).
Obesity is associated with a number of diseases including insulin resistance, glucose intolerance, dyslipidemia, and hypertension, collectively known as the metabolic syndrome or syndrome X. Patients with metabolic syndrome have a higher risk for coronary artery disease and stroke [Grundy S. M. et al. Circulation 112:e285-e290, 2005]. Epidemiologic studies have shown that treating diabetes/insulin resistance in these patients can reduce the risk of coronary artery disease. Indeed, in mouse models of atherosclerosis, TGR5 agonism was shown to reduce macrophage mediated atherosclerosis via reduction of lipid loading. Pois, et al. Cell Metabolism 14, 747-757 2011. Current strategies for reducing the risk of coronary artery disease and stroke in obese patients include treatment of diabetes and insulin resistance. Marketed drugs to treat diabetes and insulin resistance include biguanides (such as metformin), peroxisome proliferator activated receptor gamma (PPARγ) agonists (such as rosiglitazone and pioglitazone), sulphonylureas, and most recently GLP-I mimetics such as Exenatide (Byetta®). However, there remains a need for additional agents that can treat the root cause(s) of metabolic syndrome by treating obesity and diabetes. TGR5 modulators described in this invention represent such an opportunity.
Compounds and pharmaceutical compositions, certain of which have been found to modulate TGR5 are included herein, together with methods of synthesizing and using the compounds including methods for the treatment of TGR5-mediated diseases in a patient by administering the compounds.